Penicillins

ABSTRACT

A compound of the formula:   OR A PHARMACEUTICALLY ACCEPTABLE NONTOXIC SALT THEREOF WHEREIN R1 is hydrogen, straight or branched chain alkyl of one to five carbon atoms, monoaralkyl of up to eight carbon atoms, monoaryl, substituted monoaryl, or thienyl; A is a moiety of the formula:   wherein R2, R3, R4, R5, R6 and R7 are the same or different and each is hydrogen, straight or branched chain alkyl of one to five carbon atoms, monoaralkyl of up to eight carbon atoms, monoaryl, substituted monoaryl, or thienyl; B is a moiety of the formula:   WHEREIN R8, R9 and R10 are the same or different and each is hydrogen, fluorine, chlorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphonyl, sulphamyl, nitro, cyano, di(lower alkyl)amino, lower alkanoylamino, lower alkanoyloxy, lower alkylsulphonylamino, trifluoromethyl or hydroxy; E is oxygen or sulphur; and C* is a carbon atom constituting a center of chirality, ARE USEFUL FOR THEIR ANTIBACTERIAL ACTIVITY.

United States Patent 1191 Schrock et al.

[ Dec. 2, 1975 PENICILLINS Inventors: Wilfried Schrock; Karl-Georg Metzger; Hans-Bodo Konig, all of Wuppertal, Germany [73] Assignee: Bayer Aktiengesellschaft, Germany [22] Filed: Apr. 15, 1974 [21] Appl. No.: 461,227

[301 Foreign Application Priority Data Apr. 19, I973 Germany 2320039 [52] US. Cl. 260/239.l; 424/271 [51] Int. CI. C07D 499/46 [58] Field of Search 260/2391 [56] References Cited UNITED STATES PATENTS 3,433,784 [1969 Long ct al 260/239.l 3,518,253 /l970 Fosker et al. 260/239.l

FOREIGN PATENTS OR APPLICATIONS l,06l,335 1967 United Kingdom 260/239.l

Primary Examiner-Gerald A. Schwartz [57] ABSTRACT A compound of the formula:

or a pharmaceutically acceptable nontoxic salt thereof wherein R, is hydrogen, straight or branched chain alkyl of one to five carbon atoms, monoaralkyl of up to eight carbon atoms, monoaryl, substituted monoaryl, or thienyl; A is a moiety of the formula:

- R R R R R and R are the same or different and each is hydrogen, straight or branched chain alkyl of one to five carbon atoms, monoaralkyl of up to eight carbon atoms, monoaryl, substituted monoaryl, or thienyl;

B is a moiety of the formula:

67 Claims, No Drawings PENICILLINS The present invention relates to penicillins, to a process for their production, to pharmaceutical compositions useful for their antibacterial activity wherein said penicillins are the active agents, to methods of treating bacterial infections in humans and animals using said penicillins, to animal feedstuff compositions embodying said penicillins and to the use of said penicillins as.

growth promoting agents for use with animals.

It is known that acetamidopenicillanic acids which in the oz-position of the acetamido moiety carry an aryl group and an acyl semicarbazide moiety are synthetically obtainable and exhibit antibacterial activity. See British Pat. No. 1,061,335. However according to that patent, none of the penicillins disclosed have a hydrazine group of the acyl semicarbazide formed into a heterocyclic ring.

More particularly, the present invention is concerned with penicillins of the formula:

cam-cin-co-m cs I B f h W 011 coon wherein R R R R R and R are the same or different and each is hydrogen, straight or, branched chain alkyl of one to five carbon atoms, aralkyl of up to eight carbon atoms, aryl preferably monoaryl, substituted aryl preferably substituted monoaryl, or thienyl;

B is a moiety of the formula:

war-U wherein R R and R are the same or different and each is hydrogen, fluorine, chlorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphonyl, sulphamyl, nitro, cyano, di(lower alkyl)amino, lower alkanoylamino, lower alkanoyloxy, lower alkylsulphonylamino,. trifluoromethyl or hydroxy;

E is oxygen or sulphur; and

C* is a carbon atom constituting a center of chirality which may be either racemic or either of the R- or S-configurations.

These penicillins are particularly useful for their antibacterial activity.

As used herein, the phrase compounds of the present invention include both the penicillins in the form of the free acid and in the form of pharmaceutically acceptable nontoxic salts.

The preferred salts of the penicillins of the present invention include the sodium, potassium, magnesium, calcium, aluminum and ammonium salts, as well as diand tri-lower alkylamines, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, N-benzyl-B-phenethylamine, N-methylmorpholine and N-ethylmorpholine, l-ephenamine, dehydroabietylamine, N,N-bisdehydroabietylethylenediamine, N-lower alkylpiperidine, as well as other amines which are known to form salts of penicillins.

The phrase lower alkyl includes straight as well as branched chain alkyl moieties of one to six carbon atoms.

The penicillins of the present invention may be produced by reacting a compound of the formula:

wherein B and are as defined above; and either When R or R and R are as defined in (a) or (b), a R R d R are each hydrogen; or the reaction is carried out in the presence of a base or b R R i h moiety C(R14)2 and R13 is hydro buffer. When R R and R are as defined in (c) or (d), the reaction is carried out either in the presence or gen; or c R d R are each hydrogen and R3 is a tria|ky] the absence of a base or buffer. The reaction temperasilyl, preferably tri-loweralkylsilyl of the formula: ture is from 20C to about The penicillins of the present invention and their RH pharmaceutically acceptable nontoxic salts may be interconverted according to techniques which are per se known, such as for example reacting the penicillin in Rm the form of a free acid with a suitable base.

The compounds of the present invention are particuwherein R14 R15 and R16 are each lower alkyl; or 15 larly useful for their antibacterial activity especially against the family Pseudomonadaceae. The penicillins of the present invention display greater activity against Pseudomonadaceae than do such commercially available penicillins as Ampicillin and Carbenicillin.

If, for example D()-a-amino-benzylpenicillin and si R, 20 l-chlorocarbonyl-3-oxo-pyrazolidine are used as starting substances, the course of the reaction can be illustrated by the following equation:

COOH

d. R and R are trialkylsilyl, preferably triloweralkylsilyl of the formula:

COOH

wherein R R and R are as above defined; and According to one embodiment of the present inven- R is hydrogen; tion: with a compound of the formula: R is hydrogen, or straight or branched chain alkyl of one to four carbon atoms; A is a moiety of the formula:

{+1 III 2 0 IL I CEW 3 2 wherein T E R A and E are as above defined; and C=N W is halogen, azido or /CH O 3-1\l0 -O Cl -S-CH -O-N=C\ -0-N -0- -S- (lower alkyl) or III\ J o -N/ According to another embodiment of the present invention:

R is hydrogen or lower alkyl;

R C R om c R C R A is a moiety of the formula:

6 7 R C R wherein R R R R R and R are the same or different and each is hydrogen, alkyl of one to four carbon atoms, phenyl or hydroxyphenyl; B is a moiety of the formula:

and C* is in the R- configuration. -According to another embodiment of the present in- W. m. e m r o n e g o r d y .h ub t 1 wR V 5 2 A is a moiety of the formula:

4 R C R wherein R R and R are the same or different and each is hydrogen, fluorine, chlorine, bromine, iodine,

wherein 1 R R R R R and R are each hydrogen or one is methyl, ethyl, phenyl or nitrophenyl and each of kanoyloxyr lower alkylsulphonylammo mfluoro' the rest is hydrogen, or two are each methyl and methYl or hydroxythe rest are each hydrogen; According to another embodiment of the present in- B is phenyl, p hydroxyphenyl or cyclohexadiembyl; vention: and

C* is in the R- configuration.

lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphonyl, sulphamyl, nitro, cyano, di(lower alkyl)amino, lower alkanoylamino,

R,, A and B are as defined in the immediately preceding embodiment, and C* is in the R- configuration.

According to another embodiment of the present invention:

According to another embodiment of the present in- R is hydrogen, or alkyl of one or two carbon atoms;

wherein thienyl or cyclohexadi- R R R R R and R are each hydrogen or one is alkyl of one to four carbon atoms, phenyl or nitrophenyl and each of the rest is hydrogen, or two are en-l-yl. According to another embodiment of the present in- 'vention:

each methyl and each of the rest is hydrogen;

B is phenyl; phenyl substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, nitro, cyano, di(lower alkyl)amino, lower alkanoylamino, lower R A and B are as defined in the immediately preceding embodiment, and C* is in the R-configuration.

7 alkanoyloxy, sulphamyl, hydroxy or dihydroxy; cyclohexadien-l-yl; or thienyl; and C* is in the R- configuration. According to another embodiment of the present invention:

R is hydrogen or methyl; A is a moiety of the formula:

wherein R R R R R and R are each hydrogen or one is methyl, ethyl, phenyl or nitrophenyl and each of the rest is hydrogen, or two are each methyl and the rest are each hydrogen;

B is phenyl; phenyl substituted by hydroxy, methyl,

fluoro, chloro, nitro, cyano, methoxy, acetoxy, acetamido, dimethylamino, sulphamyl, or dihydroxy; cyclohexadien-l-yl; or thienyl; and

C* is in the R- configuration.

According to another embodiment of the present invention, the salt of the compound of formula I is selected from the group consisting of sodium, potassium, magnesium, calcium, aluminum, ammonium, a di(- lower alkyl)amine, a tri(lower alkyl)amine, procaine, dibenzylamine, N,N-dibenzylethylenediamine, N-benzyl-B-phenethylamine, N-methylmorpholine, N-ethylmorpholine, l-ephenamine, dehydroabietylamine, N,N-bis-dehydroabietylethylenediamine, or N-lower alkylpiperidine.

According to another embodiment of the present invention, a compound of formula I is in the form of the sodium salt wherein C* is in the R- configuration.

According to another embodiment of the present invention:

R R and R are each hydrogen, or R is hydrogen and R and R are -Si(CH and W is chlorine.

Representative compounds of formula II above which are used as starting materials in the process according to the present invention are known. Their preparation is described in German Pat. No. 1,156,078, South African Pat. No. 68/8,290, Netherlands Pat. No. 68/18,057, Belgian Pat. No. 737,451, US. Pat. Nos. 2,985,648, 3,140,282, 3,144,445, 3,157,640 and 3,342,677 and J. Chem. Soc. (C), 1971, 1920 and J. Med. Chem. 14, 117 (1971).

Compounds of the formula II which are not previously known and in which R R and R are hydrogen can be prepared, for example, from 6- aminopenicillanic acid entirely analogously to the method described in German Pat. No. 1,156,078.

Those compounds of the formula 11 wherein R mR is -C(R and R is hydrogen that are used as starting materials in the process according to the present invention, and which are not previously known, can be prepared by condensation of compounds of the formula ll wherein R R and R are hydrogen, with carbonyl compounds R .,CO-R wherein R is as defined above, with elimination of water.

Those compounds of the formula ll used as starting materials wherein R is hydrogen and R and R are trialkylsilyl or wherein R and R are hydrogen and R is trialkylsilyl can, where they are not previously known, be prepared by reaction of a compound of the formula I], wherein R R and R are hydrogen, with silylating agents, such as trimethylchlorosilane or hexamethyldisilazane, in the presence of acid-binding agents such as triethylamine.

The compounds of the present invention include the racemates, optical isomers and epimers, and all crystalline forms including the anhydrous and hydrated forms such as the mono-, diand trihydrates.

The configuration of the asymmetric centers of the 6-aminopenicillanic acid nucleus in the compounds of the formula II should be identical with that of the corresponding asymmetric centers of 6-aminopenicillanic acid which has been obtained, for example, from penicillin G by fermentative processes.

Those compounds of the formula III, used as starting materials in the process of the present invention, that have not previously been disclosed can be prepared from the corresponding heterocyclic hydrazine compound of the formula IV, such as for example pyrazolidine, and the appropriate compound of the formula W-CE-W, such as for example phosgene, in an inert organic solvent, such as for example tetrahydrofurane, or in a mixture of water and an inert organic solvent, such as for example chloroform, in the presence of a base, such as for example triethylamine.

wherein R, and A are as above defined.

Illustrations of their synthesis are provided in more detail in the following examples. However, when W is not halogen, the desired compounds of formula III can also be prepared from a compound of the formula 111 wherein W ishalogen by reaction with a compound of the fonnula l-l-W wherein W is as defined above but is not halogen, in the presence of a base such as triethylamine, and in an inert organic solvent, such as tetrahydrofuran, or a mixture of water and an inert organic solvent, such as chloroform. I

Diluents which can be used are the substances mentioned in the paragraphs which follow.

If the starting materials used for the synthesis of the compounds of the invention are compounds of formula 11 in which either (a) R R and R are hydrogen or (b) R ...R, is C(R and R is hydrogen, the reaction in the process of the invention can be carried out in, for example, a mixture of water with a water-miscible organic solvent, such as acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulphoxide or isopropanol. The pH of the reaction mixture is kept, for example, between 6.5 and 8.0 by addition of bases or use of buffer solutions. The same reaction can however also be carried out in other pl-l ranges, for example, at 4.5 to 9.0, or at pll2.0 to 4.5. It is also possible to carry out the reaction in a waterimmiscible solvent, for example chloroform or methylene chloride, with the addition of, preferably, triethylamine, diethylamine, or N-ethylpiperidine as a base. The reaction can also be carried out in a mixture of water and a water-immiscible solvent, such as ether, chloroform, methylene chloride, carbon disulphide, isobutyl methyl ketone, ethyl acetate or benzene, the mixture preferably being vigorously stirred and the pH maintained at the desired value (e.g. between 4.5 and 9.0 or 2.0 and 3.0) by the addition of a base or the use of a buffer solution. The reaction can however also be carried out in water as the sole vehicle in the absence of any organic solvent and in the presence of an organic or inorganic base or a buffer.

When a compound of the formula II is used in which two of the radicals R R and R are trialkylsilyl and the other is a hydrogen radical, the reaction must in most cases be carried out in a solvent which is anhydrous and free of hydroxyl groups, for example, methylene chloride, chloroform, benzene, tetrahydrofurane, acetone or dimethylformamide. The addition of bases is not necessary in such a case but does enable the yield and purity of the product to be improved in some cases. Admittedly, the converse effect is also possible. The optionally added base must either be a tertiary amine,

such as pyridine or triethylamine, or a secondary amine which are difficult to acylate as a result of steric hindrance, such as dicyclohexylamine. The number of bases that can be used is therefore very large.

The amount of base used is decided, for example, by the desired adherence to a certain pH. Where a pH measurement and adjustment is not carried out or, because of the absence of sufficient amounts of water in the diluent, it is not possible or not meaningful, 2 mol equivalents of base are preferably used where a compound of the formula II is used in which R R and R are all hydrogen, or R and R together are C(R and R is hydrogen, while either no base at all or, preferably, 1 mol equivalent of base is added when two of R R and R are trialkylsilyl and the other is hydrogen. i

The reaction temperature can be varied over a substantial range. The reaction is preferably carried out between and +C. As with most chemical reactions, higher or lower temperatures than those indicated in the examples can be used. However, if the values indicated there are exceeded substantially, side- ,equimolecular amounts. However, it can be desirable to use one of the two reactants in excess in order to facilitate the purification, or preparation in pure form, of the desired compound of the invention and to increase the yield.

For example, the reactants of the formula [I can be employed in an excess of 0.1 to 0.3 mol equivalents, and less decomposition of the reactants of the formula III in an aqueous solvent mixture can be achieved thereby. The excess of the reactants of the formula II can easily be removed during working up of the reaction mixture, owing to their good solubility in aqueous mineral acids.

However, it is also possible with advantage to employ the reactants of the formula III in an excess of, for exoccurs as a side-reaction in aqueous solvents, is compensat'ed for. Since the compounds of the formula Ill added in excess rapidly become converted, in water, into neutral nitrogen-containing heterocyclic compounds which can easily be removed, the purity of the compounds of the invention obtained is hardly impaired thereby.

The reaction mixture resulting from the reaction described above can be worked up in the manner generally known for penicillins.

If the starting material used is a compound of the formula H which contains a moiety C(R the hydrolytic splitting off of the fragment C(R in the form of the carbonyl compound R COR which was originally used to prepare the compound of the formula II, takes place immediately after the reaction of the compound II with the compound of the formula III if water is present in the reaction medium, or during working up of the reaction mixture under aqueous conditions, if no water is present in the reaction medium.

'If a compound of the formula II is used in which two of R R and R are trimethylsilyl moieties is used as the starting material, the hydrolytic splitting-off of the trialkylsilyl radicals takes place during working up the reaction mixtures under aqueous conditions.

The following may be mentioned individually as examples of new active compounds of the invention:

bonylamino]-benzylpenicillin:

CONH--CHCONH 5 on COOH or the sodium salt thereof.

D(-)-a-[ (4-Phenyl-5 -oxo-3-pyrazolin-2-yl )-carbonylamino]-benzylpenicillin:

or the sodium salt thereof.

D()-a- 3-Methyl-5 -oxo-3-pyrazolin-2-yl )-carbonylamino]-benzylpenicillin:

N-CO-NH-CH-OONH OH H c 3 COOH 11 or the sodium salt thereof.

D()-a-[ S-Phenyl-S-oxo-3-pyrazolin-2yl )-carbonylamino]-benzylpenicillin:

H l ir-coNn-cn-coNn 15 O (R) N K coon or the sodium salt thereof.

D()-a-[ 3-p-Nitrophenyl-5-oxo-3-pyrazolin-2-yl)- carbonylamino]-benzylpenicillin:

COOH

or the sodium salt thereof.

D(-)-a-[ 3-m-Nitrophenyl-5-oxo-3-pyrazolin-2-yl carbonylamino]-benzylpenicillin:

H ii-conn-cn-conn COOH N0 or the sodium salt thereof. I

D()-a-[ 2-Methyl-4-phenyl-5 -oxo-3-pyrazolin- 1 yl)-carbonylamino]-benzylpenicillin:

-CONH-CH-CONH N (R) K 3 coon 3 or the sodium salt thereof.

D(-)-a-[ 5-Oxo-3-pyrazolin-2-yl)-carbonylamino]- benzylpenicillin:

[I i N-CONH-CH-CONH H on coon 3 or the sodium salt thereof.

D(-)-a-[(4-Methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino]-p-hydroxy-benzylpenicillin:

n H5O n l l CH N-CONH-CH-CONH 5 (R) on coon 3 or the sodium salt thereof.

D()-a-[ 4-Methyl-5 -oxo-3-pyrazolin-2-yl )-carbonylamino]-a-(cycl0hexa-l ,4-dienl -yl )-methylpenicillin:

N-CONH-CH-CONH H coon 3 or the sodium salt thereof.

D(-)-oz- 5-Oxo-3-py razolin-Z-yl )-c arbonylamino p-hydroxy-benzylpenicillin:

40 b? C. N CONH (H)CONH 3 coon 3 or the sodium salt thereof.

D( )-a- 5-Oxo-3-py razolin-2-yl )-carbonylamino a-( cyclohexa-l ,4-dienl -yl )-methylpenicillin:

l P N-CONH-CH-CONH o cn ' COOH or the sodium salt thereof.

D()-a-[ 3-Oxo-pyrazolidinl-yl )-c arbonylamino benzylpenicillin:

13 14 O ll liIH N-CONHCH-O ONH H 0 -0 ONH-CHGONH 5 R) C 5 3 (R) 0 H CH C OOH C OOH or the sodium salt thereof. or the sodium salt thereof. D()-a-[(3-Oxo-5-phenyl-pyrazolidin-l-yl)-car- D(-)-a-[ 3-Oxo-pyrazolidinl -yl )-carbonylamin0]- bonylamino]-benzylpenicillin:

a-(cyclohexal ,4-dien- 1 -yl)-methylpenicillin:

l 5 NH f; CONH-CHO OWE F (R) N-CONH-CH-C ONH 3 cia (R) COOH or the sodium salt thereof.

5 C OOH D(-)-a-[(2,4-Dimethyl-3-oxo-pyrazolidinl -yl )-carbonylamino]-benzylpenicillin:

or the sodium salt thereof. I D()-oz-[( 3-Oxo-pyrazolidinl -yl )-carbonylamino]- 2 5 p-hydroxy-benzylpenicillin: 3 3

-CONHCH-OONH 0 (R) 0 CH I H coon 3 N-C ONH-CH-C 01m 5 or the sodium salt thereof.

D()-a-[( 1,4-Dimeth l-3-oxoyraz0lidin-2- l)-car- O CH Y P y C OOH 3 bonylamino]-benzylpenicillin:

or the sodium salt thereof.

D(-)-a-[ 3-Oxo-4-methyl-pyrazolidinl-yl)-car H g CH bonylaminol-benzylpenicillin: 5 ONH l?) C o 3 i 0 CH 0 OOH NH or the sodium salt thereof. ONH CH D()-a-[(2,5-Dimethyl-3-oxo-pyrazolidin-1-yl)-car- R) 3 bonylamino] -benzylpenicillin:

CH COOH 5 -c ONH-CH-C ONH or the sodium salt thereof.

D()-a-[( 3-Oxo-5-methyl-pyrazolidinl-yl)-car- 3 bonylamino]-benzylpenicillin: OOH

v -c ONH- H-C ONH H 0. (R) H O 000K 65 CONH '(J ;CON :1 CH3 R or the sodium salt thereof. I Q- I OH D()-a-[(3-Oxo-5,S-dimethyl-pyrazolidin-l-yl)-car- H k 3 bonylamino1-benzylpe nicillin: 3 3 C OOH or the sodium salt thereof.

D()-a-[( l ,5-Dimethyl-3-oxo-pyrazolidin-2-yl)-carbonylamino] -benzylpenicillin:

or the sodium salt thereof.

D()-a-[ 2-Methyl-3-oxo-5-phenyl-pyrazolidinl yl)-carbonylamino]-benzylpenicillin:

/CH3 CONH-CH-CONH OOH or the sodium salt thereof.

D(-)-a- 1-Methyl-3-oxo-5-phenyl-py razolidin-2- yl)-carbonylamino]-benzylpenicillin:

-CONH- H-CONH COOH or the sodium salt thereof.

bonylamino]-benzylpenicillin:

fi-com-snsmm 0H3 0 CH 5 coon 3 or the sodium salt thereof.

D(-)-a- 3-Oxo-l ,2-diaza-cyclohexanl -yl)-carbonylamino]-benzylpenicillin:

H @i-CONH-CH-CONH H cs coon or the sodium salt thereof.

D()-a-[ 3-Methyl-5-oxo- 1 ,2,4-triazolin( 3 )-2-y1)- carbonylamino]-benzylpenicillin:

-CONHCH-CONH H36 (R) COOH -a-[( 1-Methyl-3-oxo-pyrazolidin-2-yl)-caror the sodium salt thereof.

D(-)-a-[(3-Ethyl-5-oxo-1,2,4-triazolin(3)-2-yl)-carbonylamino]-benzylpenicillin:

J N'GONH-CH-CQNH CH OOH or the sodium salt thereof.

D()-a-[ 3-Phenyl-5 -oxo-1,2,4-triazolin(3)-2-yl)- or the sodium salt thereof.

D(-)-a-[(4-Methyl-3 ,5-dioxol ,2,4-triazolidin- 1-yl)- carbonylamino]-benzylpenicillin:

l 3 COOH or the sodium salt thereof. 4O D(-)-a- (4-Ethyl-3 ,5 -dioxol ,2,4-tria'zolidinl -yl carbonylamino]-benzylpenicillin:

CH3CHZ-NLNH )--1i-ooNH-oH-coim 1 or the sodium salt thereof.

D(-)-a- (4-Phenyl-3 ,S-dioxol ,2,4-triazolidinl -yl carbonylamino]-benzylpenicillin:

-CONH-CHCONH l O I or the sodium salt thereof.

D(-)-a-[(4-Methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino]-benzylpenicillin:

or the sodium salt thereof.

D()-a-[(4-Methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino]-p-hydroxy-benzylpenicillin:

-CS-NH-CH-CONH C OOH or the sodium salt thereof.

D(-)-a-[ 4-Methyl-5-oxo-3-pyrazolin- 2-yl )-thiocarbonylamino]-a-(cyclohexal ,4-dien- 1-yl)-methylpenicillin:

i'r-cs-NH- H-CONH (R) l K cooH or the sodium salt thereof.

The pharmaceutical compositions of the present invention contain a major or minor amount e.g. 99.5% to 01%, preferably 95% to 0.5% of at least one penicillin as above defined in combination with a pharmaceutically acceptable nontoxic, inert diluent or carrier, the carrier comprising one or more solid, semi-solid or liquid diluent, filler and formulation adjuvant which is nontoxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in dosage unit form; i.e., physically discrete. units containing a predetermined amount of the drup corresponding to a fraction or multiple of the dosewhich is calculated to produce the desired therapeutic response. The dosage units can contain one, two, three, four or more single doses or, alternatively, one -half, third or fourth of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to a predetermined dosage regimen, usually a whole, half, third or quarter of the daily dosage administered once, twice, three or four times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the dosage will be from 25,000 (l X l0)U per kg of body weight per day. In some instances a sufficient therapeu- 18 tic effect can be obtained at a lower dose while in others, a larger dose will be required.

Oral administration can be effected utilizing solid and liquid dosage unit forms such as powders, tablets, dragees, capsules, granulates, suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate as for example starch, lactose, sucrose, glucose or mannitol. Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture, granulating or slugging, adding a lubi'icant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally with a binder such as carboxymethyl, cellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use of a nontoxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a nontoxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a nontoxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Alternatively, a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration. Nontoxic salts and salt solutions can be added to render the injection isotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in which the compound is admixed with low melting water soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher esters as for example myristyl palmitate, or mixtures thereof.

Topical administration can be effected utilizing solid dosage unit forms such as powders or liquid or semiliquid dosage unit forms such as solutions, suspensions, ointments, pastes, creams and gels. The powders are formulated utilizing such carriers as talc, bentonite, silicic acid, polyamide powder and the like. Liquid and semiliquid formulations can utilize such carriers, in addition to those described above, as polyethylene glycol, vegetable and mineral oils, alcohols such as isopropanol and the like. Other excipients such as emulsifiers, perservatives, colorants, perfumes and the like can also be present. Formulations can also be administered as an aerosol, utilizing the usual propellants such as the chlorofluorohydrocarbons.

The preferred daily dose for oral and parenteral administration is 1.25 X to 100 X IO U of active ingredient.

The penicillins and their pharmaceutically acceptable nontoxic salts are useful not only for their broad antibacterial activity but also may be used for preventing systemic and topical bacterial infections and for treating such infections after they have occurred.

The present invention also comprises an animal feedstuff which comprises a nutritious material in combination with an anti-bacterially effective amount of a compound of the present invention. The present invention also includes the mixture of a compound of the present invention with animal fooder or drinking water in order to promote the growth of animals.

The present invention also includes pharmaceutical compositions which include one or more penicillins according to the present invention in combination with other penicillins such as, for example, Oxacillin, Dicloxacillin, Aminoglycooxidantibiotics such as Gentamicin, Kanamicin, Amikacin or Tobramicin thereby producing a still broader spectrum antibiotic composition.

According to both in vitro and in vivo data, the compounds of the present invention exhibit a strong antibacterial effect particularly against Pseudomonades.

The following results were obtained according to standard in vitro and in vivo tests.

The in vitro values were carried out as minimum inhibitory concentrations (MIC) in the test tube series dilution test in a liquid medium. The readings were taken after 24 hours incubation at 37C. The MIC is given by the non-cloudy test tube in the dilution series. It is quoted in U/ml of nutrient medium.

A whole medium of the following composition was used as the growth medium:

Lab Lemco (Oxoid) l0 Peptone (Difco) l0 NaCl 3 D(+) Dextrose (Merck) O 0 g g 8 E Buffer pH 7.4 m

I l ,00 l

The numbers here allotted to the penicillin compounds correspond to the numbers of the examples in which the preparation of the particular compound is described.

Using the test-tube dilution method, the penicillin compound of Example 1 B gave the following MIC values (in U/ml) against other bacteria:

E.coli B E.coli 26/6 Proteus marg. Proteus vulg.

Klebsiella pneum. Staph.aureus 133 Enterococcus ATCC 9790 The compounds of the invention are also active against other genera of bacteria. This is shown by the following experiment, which was carried out with the compound of Example 1.

The compound of Example 1 was diluted to ug/ml with Muller-Hinton nutrient broth, with the addition of 0.1% of glucose. The nutrient solution in each case contained 1 X 10 to 2 X 10 bacteria per millilitre. The test tubes containing this mixture were incubated for 24 hours in each case and the degree of cloudiness was subsequently determined. Freedom from cloudiness indicates that the compounds are active. At a dosage of 100 pg/ml the following bacterial cultures were free of cloudiness:

E.c0li 14; E.coli C Proteus vulgaris 1017; Klebsiella K 10; Klebsiella 63; Salmonella sp.; Shigella sp.; Enterobacter sp.; Serratia sp.; Proteus, indole-negative, sp.; Proteus, indole-positive, sp.; Pasteurella pseudotuberculosis; Brucella sp.; Haemophilus influenzae; Bordetella bronchiseptica; Bacteroides sp., Staphylococcus aureus 133; Neisseria catarrhalis sp.; Diplococcus pneumoniae sp.; Streptococcus pyogenes W; Enterococcus sp.; Lactobacillus sp.; Corynebacterium diphteriae gravis; Corynebacterium pyogenes M; Clostridium botulinium;

Closzria'ium tetani', Borrelia sp.; Pseudomonas aerugi- Table ll Animal experiments with white mice: Determination of the ED, after 24 hours.

Therapy: 1 administration: 30 minutes after infection; 4 administrations: 30 minutes, 2 hours. 4 hours and 6 hours after infection The ED is a dose at which 50% of the infected animals still survive after 24 hours.

The oz-aminobenzylpenicillin used in the examples which follow contained about 14% of water but anhydrous a-aminobenzylpenicillin [compare US. Pat. No. 3,144,445] can be used equally well.

The a-amino-p-hydroxybenzylpenicillin used in the examples contained about 13% of water, but anhydrous a-amino-p-hydroxybenzylpenicillin can be used equally well.

Ampicillin is a-aminobenzylpenicillin with the D('-)- R configuration in the side chain, Amoxicillin is a-amino-p-hydroxy-benzylpenicillin with the D() R- configuration in the side chain and Epicillin is a-amino-a-( l,4-cyclohexadien-1-yl)-methylpenicillin with the D(-)- R-- configuration in the side chain.

The NMR spectra of the penicillin compounds were recorded in CD OD solution. The codes in brackets denote the following:

singlet m multiplet d doublet AB AB-system t triplet J coupling constant q quartet The IR spectra of the penicillin compound were recorded in Nujol suspension.

The following non-limitative examples more particularly illustrate the present invention.

EXAMPLE 1 11 parts by weight of phosgene were added, while stirring and cooling with ice, to a solution of 9.8 parts by weight of 4-methyl-5-oxo-pyrazoline-2 in 100 parts by volume of anhydrous tetrahydrofurane, the mixture was stirred for 30 minutes at 0C and 1 hour at room temperature and again cooled to 0C, 10.1 parts by weight of triethylamine were added dropwise over the course of 20 minutes and the mixture was stirred for a further 30 minutes at 0C and then for 2 hours at room temperature. The triethylamine hydrochloride while precipitated was filtered off and washed with dry tetrahydrofurane and the combined solutions were evaporated to dryness in vacuo.

Crude yield: 15 parts by weight of 2-chlorocarbonyl- 4-methyl-5-o xo-pyrazoline-3 The crude product was recrystallized from acetone.

Yield: 5.5 parts by weight 34% of theory; melting point 169C.

A further 1.8 parts by weight (11.2% of theory) of melting point 155C could'be isolated from the mother liquor.

Calculated: C 37.4 H 3.1 CI 22.1 N 17.4

Found: C 37.7 H 3.4 Cl 22.0 N 17.4

IR bands at 3,120, 1,750, 1,628, 1,535, 875 and 790 cm (in Nujol).

NMR signals (in CDCl at 'r=0.05 (s, 1H); 2.2 (q, J- 1H2, 1H) and 7.9 ppm (d, J- lHz, 3H).

- 11 e, t W

N-CO-NH- H-CONH OONa 3.5 parts by weight of 2-chlorocarbonyl-4-methyl-5- oxo-pyrazoline-3 were added in portions over the course of 15 minutes to a solution of 9.3 parts by weight of Ampicillin in parts by volume of 80% strength aqueous tetrahydrofurane (pH 8.2, adjusted with triethylamine), while cooling with ice and stirring, the pH being kept constant at between 7 and 8 by simultaneous addition of triethylamine.

The mixture was further stirred at room temperature until it was no longer necessary to add triethylamine to maintain the pH value of 6-7 (about 15 minutes). 50 parts by volume of water were then added, the tetrahydrofurane was stripped off in vacuo on a rotary evaporator and the aqueous solution was extracted once with ethyl acetate, which was discarded, and then covered with fresh ethyl acetate, cooled to 0C and acidified to pH 1.5 with dilute hydrochloric acid, while stirring vigorously. The ethyl acetate was separated off, the residue was extracted twice more with ethyl acetate and the combined ethyl acetate phases were washed with water and dried over M gSO After filtration, about 23 parts by volume of a 1 molar solution of sodium 2- ethylhexanoate in ether containing methanol were added, the mixture was concentrated to a small volume in vacuo at room temperature and dissolved as rapidly as possible in the requisite amount of methanol, and the solution was poured into about 500 parts by volume of ice-cold ether, containing 10% of methanol, while stirring. The mixture was allowed to settle out for 30 minutes and the product was filtered off, again suspended in ether and again filtered off. The product was then dried for 2 days in vacuo in a desiccator over P 0 and paraffin chips.

Yield: 100% of sodium D()-a-[(4-methyl-5-oxo-3- pyrazolin-2-yl)-carbonylamino]-benzylpenicillin.

B-Lactam content: 96%.

IR bands at 3,300, 1,755, 1,665, 1,598 and 1,370 cm (in Nujol).

NMR signals at 'r= 2.25 (s, 1H); 2.4-2.8 (m, 5H); 4.3 (s, 1H); 4.5 (AB, J=4Hz, 2H); 5.8 (s, 1H); 8.0 (s, 3H); 8.45 (s, 31-1) and 8.5 ppm (s, 31-1).

EXAMPLE 2 The product described in Offe et a1. [Z. Naturforsch. 7b, 446 (1952)] was obtained in 91% yield by dropwise addition of hydrazine hydrate (3.75 parts by weight) to a solution of 13.4 parts by weight of a-formyl-phenylacetic ester in 25 parts by volume of THF at C, followed by boiling for 2 hours under reflux, evaporation to dryness and recrystallization from ethanol. 4-Phenyl- 5-oxo-pyrazoline-2. Melting point 231C.

1R bands at 3,200, 3,105, 3,450-2,400, 1,612, 1,585, 1,515, 1,304, 1,277, 1,169 and 707 cm (in Nujol).

Calculated: C 67.4 H 5.0 N 17.5

Found: C 66.6 H 4.8 N 17.9

This was prepared from 9.6 parts by weight of 4-phenyl-5-oxo-pyrazolin-2 and 6.6 parts by weight of phosgene in the presence of triethylamine, as described in Example 1A. Instead of distilling the product, it was recrystallized from acetone/pentane.

Yield: 82% of 2-chlorocarbonyl-4-phenyl-5- oxopyrazo1ine-3.

Calculated: C 54.0 H 3.15 Cl 16.0 N 12.6

Found: C 54.2 H 3.2 C1 14.2 N 12.3

1R bands at 1,745, 1,715, 1,205, 881 and 766 cm (in Nujol).

ll-CO-NH-CH-CONH CH COONa 24 This was prepared from 6.5 parts by weight of 2- chlorocarbonyl-4-phenyl-5-oxo-pyrazoline-3 and 12.9 parts by weight of Ampicillin, as described in Example 1B.

Yield: 84% of sodium D() -a-[(4-phenyl-5-oxo-3- pyrazolin-2-yl)-carbonylamino]-penzylpenicillin.

Penicillin content: 93% (according to the NMR spectrum), 84% (according to analytical Craig distribution). Calculated: *C 53.8 H 4.7 N 11.8 S 5.4 Found: C 53.3 H 4.9 N 11.6 S 6.0 (In the calculation, the presence of 3.9% of water, 1.1% cf ether, 0.4% of ethyl acetate and 1.25% of sodium 2-ethylhexanoate, determined by NMR spectroscopy, was taken into account). IR bands at 3,300, 1,772, 1,682, 1,615, 1,512, 1,320 and 1,260-1,220 cm. I

NMR signals at 1' 1.7 (s, 1H); 2.1-2.8 (m, 10H); 4.25 (s, 1H); 4.45 (AB, J=4Hz, 2H); 5.75 (s, 1H) and 8.45 ppm (d,8v 2H2, 6H).

EXAMPLE 3 chlorocarbonyl-3-methyl-5-oxo-pyrazoline-3 and 62% of carbonyl-di-(3-methyl-5-oxo-2,5-dihydropyrazol- 2-ide).

KN on N\C0'/* H IR band at 1.780 cm" (in Nujol).

Calculated: C 44.2 H 4.0 Cl 8.4 N 22.0

Found: C 44.0 H 3.2 Cl 8.1 N 19.2

Reaction of the mixture with ampicillin, in the manner described in Example 1B, gave the following penicillin:

li-co-NH-cH-com CH3 Calculated: *C 48.3 H 5.2 N 12.4 S 5.7

Found: C 48.3 H 5.4 N 12.3 S 6.4 *(The presence of 1.2% of methanol, 0.63% of ether, 5.9% of water and 4.4% of sodium 2-ethylhexanoate, determined by NMR spectroscopy, was taken into account in the calculation).

Sodium D()-a-[(3-methyl-5-oxo-3-pyrazolin-2-yl)- carbonylamino]-benzylpenicillin.

1R bands at 3,300, 1,772, 1,710, 1,680, 1,608, 1,500 and 1,332 cm.

NMR signals at 'r=2.32.8 (m, 5H), 4.3 (s), 4.36 (s), 4.5 (AB, J 4H2) (a total of 4H); 5.8 (s, 1H); 7.5 (s, 3H), 8.4 (s) and 8.48 ppm (s) (a total of 6H).

B-Lactam content: 94% (iodometric determination), 88% (according to the NMR spectrum).

EXAMPLE 4 This was obtained from hydrazine hydrate and benzoylacetic ester by the procedure of Example 2A, the yield being 56% after recrystallization from ethanol: 3-phenyl-5-oxo-pyrazoline-2. Melting point 238C.

Calculated: C 67.5 H 5.0 N 17.5

Found: C 67.2 H 5.0 N 17.5

1R bands at 3,4002,000, 1,627, 1,598, 1,082, 943 and 750 cm (in Nujol).

\CONHCHCONH CH IE1 CH COONa In order to produce the requisite carbonyl-bis-[3- phenyl-S-oxo-3-pyrazolinide-(2)] (a), the product of Example 4A was silylated and subsequently reacted with phosgene. The crude product was boiled with acetone. The residue showed a strong carbonyl band in the IR spectrum, at 1,790 cm".

1R bands at 1,770, 1,680, 1,605, 1,550 and 1,335 cm.

NMR signals at r 2.1-2.9 (m, 11H); 4.3 (s), 4.54 (AB, J= 41-12), (a total of 3H); 5.8 (s, 1H); 8.43 8.51

ppm ((1, 6H).

EXAMPLE 5 This was obtained from hydrazine hydrate and pnitrobenzoylacetic ester by the procedure of Example 2A, the yield being 61% after recrystallization from ethanol. Melting point 241C. 3-(p-Nitrophenyl)-5- oxo-pyrazoline-2.

Calculated: C 52.7 H 3.4 N 20.5

Found: C 52.1 H 3.5 N 20.5

1R bands at 3,370, 3,280, 3,110, 3,080, 1,603, 1,576, 1,512, 1,340, 1,120, 1,020, 865, 795 and 762 cm (in Nujol).

-CONH-CH-CONH In order to prepare the requisite carbonyl-bis-[3-pnitrophenyl-5-oxo-3-pyrazolinide-(2)] (a), the product of Example 5A was silylated and subsequently reacted with phosgene. The crude product first obtained was then boiled with acetone. The residue which remained showed a strong carbonyl band in the IR spectrum at 1,800 cm.

Calculated: C 52.2 H 2.8 Cl 0.0 N 19.3

Found: C 53.1 H 3.0 C10.7 N 17.2

Reaction with Ampicillin by the procedure of Example 18 gave sodium D(-)-a-[(3-p-nitrophenyl-5-ox0- pyrazolin( 3 )-2-yl )-carbonylamino]-benzylpenicillin in about 100% yield.

Penicillin content according to NMR and IR spectrum: 80-90%.

Calculated: (the presence of 8.2% of water, 2.0% of ethyl acetate, 2.0% of sodium ethylhexanoate and 0.8% of ether, determined by NMR spectroscopy, was taken in account): C 47.9 H 4.7 N 12.1 S 4.6

Found: C 47.3 H 4.7 N 12.1 S 4.6

IR bands at 1,762, 1,678, 1,600, 1,520 and 1,345

NMR signals at r 1.8 2.05 (AB, J 9H2, 2H

2H); 2.3-2.8 (m, 6H); 4.25 (s) 4.5 (AB, J 4H2), (a total of 3H); 5.75 (s, 1H); 8.4 8.5 ppm (d, 6H).

EXAMPLE 6 270C. 3-( m-Nitrophenyl )-5- CH M,

The requisite 2-chlorocarbonyl-3-m-nitrophenyl-S- oxo-pyrazoline-(3) was obtained from the product of Example 6A by silylation and subsequent reaction with phosgene, the crude product first obtained being boiled with acetone. The acetone solution on evaporation gave a non-crystalline solid which according to chlorine analysis was of 47% strength. Since a strong band was present in the IR spectrum at 1,8l0-1,730 cm, the material was reacted with Ampicillin in accordance with the procedure of Example 13. The sodium D()- a- 3-m-nitrophenyl-5-oxo-pyrazolin( 3 )-2-yl )-carbonylamino]-benzylpenicil1in thereby obtained in 14% yield had the structure according to the NMR spectrum.

Penicillin content according to IR and NMR spectrum about IR bands at 3,280, 1,772, 1,717, 1,643, 1,525, 1,347 and 1,210 cm.

NMR signals at 'r= 1.5 (s, 1H); 1.9 (d, 2H); 2.33.0 (m, 7H); 4.3 (s), 4.5 (AB, J=4Hz) (a total of 3H); 5.7 (s, 1H); 8.4 8.5 ppm (d, 6H).

EXAMPLE 7 ,cocl

This was prepared from 2-methyl-4-phenyl-5- oxopyrazoline as described in Example 1A and recrys- I, tallized from benzene/petroleum ether. Yield: 76% of 1-chlorocarbonyl-2-methyl-4-phenyl- 5-oxo-pyrazoline-3, melting point 111C.

Calculated: C 55.9 1-1 3.8 CI 15.0 N 13.5

Found: C 56.3 1-1 4.0 Cl 13.3 N 12.3

1R bands at 3,080, 1,779, 1,750, 1,680, 1,226, 1,206, 890, 781 and 697 cm (in Nujol).

NMR signals at -r 1.8 (s, 1H); 2.0-2.3 (m, 21-1);

v 2.4-2.8 (m, 31-1) and 6.33 ppm (s, 31-1).

The compound was obtained in 61% yield from the product of Example 73 in the manner described'in Example 18.

pyrazolin- 1 -yl)-carbony1amino]-benzylpenicillin.

1R bands at 1,776, 1,762, 1,722, 1,605, 1,330 and 1,212 cm. NMR signals at -r= 2.3 (s, 1H); 2.4-2.75 (m, 101-1); 4.4-4.65 (m, 31-1); 5.7 (s, 1H) and 8.44 ppm '(s, 6H). 1

EXAMPLE 8 S CONE-CH-CO-NH Coons This was obtained in 94% yield from 2.0 parts by weight of Amoxicillin and 0.74 part by weight of the product of Example 1A, in the manner described in Example 1B.

Sodium D()-a-[(4-methyl-5-oxo-3-pyrazolin-2-yl)- carbonylamino]-p-hydroxybenzylpenicillin.

Penicillin content according to IR and NMR spectrum 90%.

IR bands at 3,300, 1,765, 1,720, 1,660, 1,605, 1,530 and 1,282 cm".

NMR signals at 1'= 2.3 (s, 1H); 2.7 3.2 (AB, .1 8.3

Hz, 2H 21-1); 4.49 (s), 4.52 (AB, .1 41-12) (a total of EXAMPLE 9 This was prepared in 71% yield from 1.25 parts by weight of D(-)-a-amino-a-(cyclohexa-1,4-dien-l-yl)- methylpenicillin (Epicillin) and 0.6 part by weight of the product of Example 1A, in the manner described in Example 13. Sodium D(--)-a-[(4-methy1-5-oxo-3- pyrazolin-2-yl )-carbonylamino]-a-( cyclohexa-l ,4- dienl -yl -methylpenici1lin.

Penicillin content according to IR and NMR spectrum 1R bands at 1,767, 1,665, 1,607, 1,515, 1,320, 1,217 and 976 cm".

NMR signals at -r=2.33 (s, 1H); 4.1 (s, 1H); 4.3 (s, 2H); 4.5 (s, 2H); 5.0 (s, 1H); 5.8 (s, 1H); 7.27 (s, 4H); 8.05 (s, 31-1) and 8.35 8.43 ppm (d, 6H).

EXAMPLE 10 This was prepared analogously to the literature data (Ber. 84, 10 (1951) from acrylic ester and hydrazine hydrate Oil. Pyrazo1idin-3-one,

Calculated: C 41.9 H 7.0 N 32.5

Found: C 40.7 H 6.9 N 32.5

1R bands at 3,200, 2,950, 1,725-1,640, 1,400, 1,304 and 1,198 cm" (undiluted material).

NMR signals in CDCl;, at 1'=4.1 (s, 2H); 6.45 (t, 2H) and 7.45 ppm (t, 21-1).

A mixture, cooled to 0C, of 10 parts by weight of pyrazolidinone-3, 30 parts by volume of water, 17 parts by weight of Nal-ICO and 20 parts by weight of phosgene in 200 parts by volume of chloroform was vigorously stirred for 15 minutes, the chloroform was separated off and the aqueous phase was again thoroughly stirred with 200 parts by volume of chloroform. The combined chloroform phases were dried over MgSO the solvent was stripped off in vacuo and the product was recrystallized from acteonelpetroleum ether.

| p ir-c O-NH-CH-C om: CH

This was prepared in 35% yield from Ampicillin and 1 1, the product of Example B, in the manner described in Example 1B.

Sodium D(-)-a-[( 3-oxo-pyrazolidinl-yl)-car-. bonylamino]-benzylpenicillin. u Penicillin content according to NMR and IR spectrum 90%. f. 1R bands at 3,300, 1,770, 1,665, 1,605, 1,530, 1,330 and 1,240 cm". 5 1 NMR signals at 1- 2.4-2.8 (m, 5H); 4.5 (s); 4.53 (AB,.] 41-12) (a total of 31-1); 5.83 (s), 6.0 (t, J 81-12) 1 1 (a total of 31-1); 7.4 (t, .1 81-12, 21-1); 8.4 8.5 pp, (d,

EXAMPLE 1 l w E 6 N11 1-GOCl 10.8 parts hy weight of 4-methylepyrazolidin-3-one were initially introducedinto; parts by volume of tetrahydrofurane, 10.9 parts by weight of phosgene in 20 parts by volume of te'trahydrofurane were added dropwise at 0C, the mixture was stirred for 30 minutes at 0C, 10.1 parts by weight of triethylamine, were then added dropwise,.the mixturewas stirred for 30 minutes at 0C and 1 hour. at room temperatureand' filtered, the filtrate was evaporated to dryness and the product was recrystallized from" acetone, filtered off' and .washed with ether. 1

Yield: 34% of l-chlorocarbonyl 3.aoxo-4-methylpyrazolidine, melting point C.

Calculated: C 37.0 H 4.3 Cl 2l.8.N'l7;.2

Found: C 37.4 1-1 4.4 C1213 N 16.6

1R bands at 3,270-2,400, 1,735, 1,318, 990 and 788 cm (in Nujol).

This was prepared from 5.2 parts by' weight of lchlorocarbonyl-3-oxo-4-methyl-pyrazolidine and 14.1 parts by weight of Ampicil-lin asdes'c'ribedin Example 1B.

A part of the product was obtained as free penicillic acid, which was sparingly soluble in ethyl acetate and water and which was converted into the sodium-salt of the penicillin by dissolving in dimethylacetamide, adding sodium ethylhexano ate and precipitating the product with ether. Yield 42% of sodium D(-)=a-[(3-oxo-4- methyl-pyrazolidinl -yl )-carbonylami no] -benzylpenicillin. I i

A further fraction of the sodium salt was obtained from the ethyl acetate extract (as in Example 1B).

Yield: 38%.

Calculated; (the presence of 3.6% of water, 2.2% of ether and 0.7% of sodium Z-ethylhexanoate, determined by NMR spectroscopy, taken into ac-. count in the calculation): C 4911-1 5' N -13.23 6.0-

EXAMPLE 12 N-COC].

This was prepared as described in Example 118 from 10.8 parts by weight of S-methyl-pyrazolidin-3-one. Recrystallization from acetone. l-Chlorocarbonyl-3- oxo-imethyl-pyrazolidine. Melting point 143C. Yield: 39%.

Calculated: C 36.9 H 4.3 Cl 21.9 N 17.2

Found: C 37.5 H 4.4 Cl 21.6 N 17.2

IR bands at 3,300-2,200 and l,7601,640 cm (in Nujol).

l H -co-rm-c(z%conn s cs 3 l ELK This was prepared in 94% yield from 6.1 parts by weight of 1-chlorocarbonyl-3-oxo-5-methy1-pyrazolidine and 16.5 parts by weight of Ampicillin, as described in Example 1B.

Sodium D(-)-a-[(3-oxo-5-methy1-pyrazo1idin-1-yl)- carbonylamino]-benzylpenici11in.

34 Penicillin content according to NMR and IR spectrum: 90%.

Calculated: (the presence of water (3.3%), sodium ethyl-hexanoate (2.5%), ether (2.3%) and methanol (1.3%), determined by NMR spectroscopy, was taken into account in the calculation). C 49.3 H 5.4 N 12.8 S 5.8

Found: C 47.7 H 5.4 N 12.8 S 6.0

IR bands at 1,770, l,700l,600, 1,522, 1,335 and NMR signals at 1' 2.4-2.8 (m, 5H); 4.47 (s), 4.5 (AB, J 4H2), (a total of 3H); 4.9-5.6 (m, 1H); 5.8 (s, 1H); 6.8-7.4 (m, 1H); 7.9 (d, 1H); 8.4 (S, 3H); 8.5 (s, 3H) and 8.7 ppm ((1, J 6H2, 3H).

EXAMPLE 1 3 This was prepared according to Ber. 84, 10 (1951) from B-dimethylacrylic acid ethyl ester. Boiling point l03 105C. The substance crystallized after some hours. 5,5-Dimethyl-pyrazolidin-3-one. Melting point 6162C.

Yield 82%.

Calculated: C 52.7 H 8.8 N 24.6

Found: C 52.9 H 8.9 N 24.7

1R bands at 3,180, 1,675, 1,289, 1,275, 1,145, 1,038, 1,010, 983, 899 and 801 cm" (in Nujol).

NMR signals at 1- 3.5 (broad signal, 2H); 7.6 (s, 2H) and 8.65 ppm (s, 6H).

This was obtained from 5,5-dimethyl-pyrazo1idin- 3-one as describedin Example 11B, the yield being 74% after recrystallization from benzene/petroleum ether. 1 -Chlorocarbony1- 3-oxo-5,S-dimethyl-pyrazolidine. Melting point C.

Calculated: C 40.8 H 5.1 C1 20.1 N 15.9

Found: C 41.5 H 5.3 (120.1 N 15.7

IR bands at 3,2502,250, 1,750, 1,7251,690, 1,332, 1,290, 1,180 and 800 cm (in Nujol).

NH lr-co-mr-cu-conn This was prepared as described in Example 18 from IR bands at 1 3 K740416881 1,332 1,244 8.8 parts by weight of 1-chlorocarbonyl-3-oxo-5,5- 1,182, 990, 824 and 707 cnfl j dimethyl-pyrazolidine and 21.4 parts by weight of Amplicillin.

Sodium D()-a-[(3-oxo-5 ,S-dimethyl-pyrazolidin-1- yl )-carbonylamino]-benzylpenicillin.

Yield: 86% (C) Penicillin content according to NMR and IR spectrum: 95%.

Calculated: (the presence of water (2.5%) and ether (2.3%), determined by NMR spectroscopy, was taken into account): C 50.6 H 5.5 N 13.0 S 6.0

NH CH Found: C 50.0 H 6.1 N 12.8 S 6.0 N-CO-NH CH-CONH 5 IR bands at 3,300, 1,770, 1,700, 1,615, 1,520, 1,305 (R) and 1,180 cm. CH

NMR signals at 1' 2.3-2.8 (m, 5H); 4.5 (AB, J COONa 3 4H2) and 4.55 (s) (a total of 3H); 5.8 (s, 1H); 7.3 (s,

2H); 8.4 (s), 8.5 (s), and 8.52 ppm (s) (a total of 12H).

EXAMPLE 14 This was prepared as described in Example 1B from (A) 5 11.2 parts by weight of 1-chlorocarbonyl-3-oxo-5- phenylpyrazolidine and 21 parts by weight of Ampicillin.

Yield: 82% of sodium D()-a-[(3-oxo-5-phenyl- H pyrazolidin-1-yl)-carbonylamino]-benzylpenicillin.

H Calculated: (the presence of water (3.5%), ether (1.3%) and methanol (0.9%), determined by NMR spectroscopy, was taken into account): C 53.9 H 5.1 N 11.8 S 5.4 Found: C 53.0 H 5.6 N 11.8 S 5.4 IR bands at 3,275, 1,765, 1,660 and 1,607 cm'. This was prepared according to Ber. 84, 10 (1951) NMR signals at 1' 2.3-2.9 (m, 10H); 4.146 (m, from cinnamic acid ethyl ester and recrystallized from 4H); 5.8 (s, 1H); 6.4-7.0 (m, 1H); 7.3-7.8 (m, 1H); benzene and subsequently from isopropanol. S-Phenyland 8.4 ppm (d, 6H). pyrazolidin-3-one.

Yield: 51%. Melting point 104C. 40 EXAMPLE 15 Calculated: C 66.7 H 6.2 N 17.3 Found: C 66.1 H 6.4 N 17.3 IR bands at 3,6002,500, 3,160, 1,710, 1,660, 1,080, 0 966, 943 and 707 cm (in Nujol). H 0 CH NMR signals at 1'= 2.66 (s, 5H); 5.3 (t, .1 approx. 8.5 5 Hz, 1H); 7.3 (2 d, J, 7.8 Hz, J 9.2 Hz, 2H). H

' CH 1: d H i1 -c 001 H I.

This was prepared analogously to Example 10A from 10.0 parts by weight of methacrylic ester and 5.5 parts This was prepared as described in Example 11B from by weight of methylhydrazine. Boiling point, 5-phenylpyrazolidin-3-one. l-Chlorocarbonyl-3-oxo-5- 1 12-1 14C. phenylpyrazolidine, obtained in 74% yield, melted at Yield: 84% of 1,4- and 2,4-dimethy1-5-oxo-pyrazoli- 146C and showed the correct analysis. dine.

Calculated: C 53.5 H 4.4 Cl 15.8 N 12.5 Calculated: C 52.7 H 8.8 N 24.6 Found: C 54.1 H 5.0 Cl 15.3 N 12.5 Found: C 49.5? H 9.0 N 24.7

IR bands at 3,7002,500, 3,200, 2,970, 2,940, 2870 and 1,684 cm (undiluted material).

The N-CH signals at 697(1) and 7.357 (11) in the NMR spectrum indicate amixture of 12% ofI and 88% of II.

NMR signals at 'r= 1.5 (very broad signal, integration not meaningful); 6.26.7 (m, 1H); 6.7-7.6 (m) and 6.9 (s) and 7.35 (s) (a total of 5H) and 8.8 ppm (d, J 6I-Iz, 3H).

O H C coc1 O CH -CONHCH-C ONH- CH COONa 0 CH 1 CO-NH4CH--C0NH 3 This was obtained from 9 parts by weight of the mixture of substances obtained in Example 15B and 20.2 parts by weight of Ampicillin.

Yield: 44% of a mixture of sodium D()-a-[(1,4- dimethyl- 5-oxo-pyrazolidin-2-yl)-carbonylamino]-benzy1penicillin (I) and sodium D()-a-[(2,4-dimethyl-5-oxopyrazolidin-1-y1)-carbony1amino]-benzylpenicil1in (II Penicillin content according to IR and NMR spectrum 80-90%.

Calculated: (the presence of water (2.8%), ether (0.75%) and sodium ethylhexanoate (2.9%), determined by NMR spectroscopy, was taken into ac count): C 50.6 H 5.5 N 12.8 S 5.9

Found: C 50.4 H 6.2 N 12.9 S 6.3

IR bands at 3,255, 1,770,1,755,1,718, 1,654, 1,610, 1,510 and 1,240 cm.

NMR signals at 1' 2.4-2.8 (m, 5H); 4.34.6 (m, 3H); 5.8 (s, 1H); 6.2-7.0 (m), 6.85 (s), 7.25 (s), 77.6 (m) (a total of 6H); 8.4 (s) and 8.5 (s) (a total 0f6 H); and 8.7-9.0 ppm, (m, 3H).

The integration of the two N-CH signals at r 6.85 (I) and 7.25 (II) indicates a ratio 1:11 of 1:3.

EXAMPLE 16 H CH H I 3 cn This was prepared analogously to Example 10A from 1 1.4 parts by weight of crotonic acid ethyl ester and 5.5

parts by weight of methylhydrazine.

Boiling pointm 87C.

Yield: 91% of a mixture of 1,3-dimethy1-5-oxopyrazolidine (I) and 2,3-dimethyl-5-oxo-pyrazolidine (II).

Calculated: C 52.7 H 8.8 N 24.6

Found: C 52.2 H 8.7 N 24.5

IR bands at 3,150, 2,970, 2,870, l,460-1,340 cm l ,680 and 

1. A COMPOUNT OF THE FORMULA
 2. A compound according to claim 1 wherein R1 is hydrogen, or straight or branched chain alkyl of one to four carbon atoms; R2 and R3 are the same or different and each is hydrogen, alkyl of one to four carbon atoms, phenyl or hydroxyphenyl; B is a moiety of the formula:
 3. A compound according to claim 2 wherein C* is in the R-configuration.
 4. A compound according to claim 1 wherein R1 is hydrogen; R2 and R3 are the same or different and each is hydrogen or methyl; B is phenyl, hydroxyphenyl, thienyl or cyclohexadien-1-yl.
 5. A compound according to claim 4 wherein C* is in the R-configuration.
 6. A compound according to claim 1 wherein R1 is hydrogen or lower alkyl; R2 and R3 are each hydrogen, or one is alkyl of one to four carbon atoms, phenyl or nitrophenyl and the rest are each hydrogen, or two are each methyl and the rest are each hydrogen; B is phenyl, hydroxyphenyl or cyclohexadien-1-yl; and C* is in the R- configuration.
 7. A compound according to claim 1 wherein R1 is hydrogen or methyl; R2 and R3 are each hydrogen or one is methyl, ethyl, phenyl or nitrophenyl and each of the rest is hydrogen, or two are each methyl and the rest are each hydrogen; B is phenyl, p-hydroxyphenyl or cyclohexadien-1-yl; and C* is in the R- configuration.
 8. A compound according to claim 1 wherein R1 is hydrogen, or alkyl or one or two carbon atoms; R2 and R3 are each hydrogen or one is alkyl of one to four carbon atoms, phenyl or nitrophenyl and each of the rest is hydrogen, or two are each methyl and each of the rest is hydrogen; B is phenyl; phenyl substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, nitro, cyano, di(lower alkyl)amino, lower alkanoylamino, lower alkanoyloxy, sulphamyl, hydroxy or dihydroxy; cyclohexadien-1-yl; or thienyl; and C* is in the R- configuration.
 9. A compound according to claim 1 wherein R1 is hydrogen or methyl; R2 and R3 are each hydrogen or one is methyl, ethyl, phenyl or nitrophenyl and each of the rest is hydrogen, or two are each methyl and the rest are each hydrogen; B is phenyl; phenyl substituted by hydroxy, methyl, fluoro, chloro, nitro, cyano, methoxy, acetoxy, acetamido, dimethylamino, sulphamyl, or dihydroxy; cyclohexadien-1-yl; or thienyl; and C* is in the R- configuration.
 10. A salt of a compound of claim 1 wherein the salt is selected from the group consisting of sodium, potassium, magnesium, calcium, aluminum, ammonium, a di(lower alkyl)amine, a tri(lower alkyl)amine, procaine, dibenzylamine, N,N''-dibenzylethylenediamine, N-benzyl- Beta -phenethylamine, N-methylmorpholine, N-ethylmorpholine, 1-ephenamine, dehydroabietylamine, N,N''-bis-dehydroabietylethylenediamine, or N-lower alkylpiperidine.
 11. A compound according to claim 1 in the form of the sodium salt wherein C* is in the R- configuration.
 12. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 13. The compound according to claim 1 which is D(-)- Alpha -((4-phenyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 14. The compound according to claim 1 which is D(-)- Alpha -((3-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 15. The compound according to claim 1 which is D(-)- Alpha -((3-phenyl-5-oxo-pyrazolin-(3)-2-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 16. The compound according to claim 1 which is D(-)- Alpha -((3-p-nitrophenyl-5-oxo-pyrazolin(3)-2-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 17. The compound according to claim 1 which is D(-)- Alpha -((3-m-nitrophenyl-5-oxo-pyrazolin(3)-2-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 18. The compound according to claim 1 which is D(-)- Alpha -((2-methyl-4-phenyl-5-oxo-3-pyrazolin-1-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 19. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-hydroxybenzylpenicillin or the sodium salt thereof.
 20. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)- Alpha -(cyclohexa-1,4-dien-1-yl)-methylpenicillin or the sodium salt thereof.
 21. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-m-methyl-benzylpenicillin or the sodium salt thereof.
 22. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-methyl-benzylpenicillin or the sodium salt thereof.
 23. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-o-fluoro-benzylpenicillin or the sodium salt thereof.
 24. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-m-fluoro-benzylpenicillin or the sodium salt thereof.
 25. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-fluoro-benzylpenicillin or the sodium salt thereof.
 26. The compound according to claim 1 which is D(-)- Alpha -((4-metHyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-m-chloro-benzylpenicillin or the sodium salt thereof.
 27. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-chloro-benzylpenicillin or the sodium salt thereof.
 28. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-nitro-benzylpenicillin or the sodium salt thereof.
 29. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-chloro-benzylpenicillin or the sodium salt thereof.
 30. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-nitro-benzylpenicillin or the sodium salt thereof.
 31. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-cyano-benzylpenicillin or the sodium salt thereof.
 32. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-m-methoxy -benzylpenicillin or the sodium salt thereof.
 33. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-methoxy -benzylpenicillin or the sodium salt thereof.
 34. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-m-hydroxy -benzylpenicillin or the sodium salt thereof.
 35. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-m,p-dihydroxy -benzylpenicillin or the sodium salt thereof.
 36. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-acetoxy -benzylpenicillin or the sodium salt thereof.
 37. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-acetamido -benzylpenicillin or the sodium salt thereof.
 38. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-dimethylamino -benzylpenicillin or the sodium salt thereof.
 39. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-sulphamyl -benzylpenicillin or the sodium salt thereof.
 40. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)- Alpha -2-thienyl-methylpenicillin or the sodium salt thereof.
 41. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)- Alpha -3-thienyl-methylpenicillin or the sodium salt thereof.
 42. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-hydroxy-benzylpenicillin or the sodium salt thereof.
 43. The compound according to claim 1 which is D(-)- Alpha -((3-methyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-hydroxy -benzylpenicillin or the sodium salt thereof.
 44. The compound according to claim 1 which is D(-)- Alpha -((4-phenyl-5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-hydroxy -benzylpenicillin or the sodium salt thereof.
 45. The compound according to claim 1 which is D(-)- Alpha -((3-methyl-5-oxo-pyrazolin-2-yl)-carbonylamino)- Alpha -(1,4-cyclohexadien-1-yl)-methylpenicillin or the sodium salt thereof.
 46. The compound according to claim 1 which is D(-)- Alpha -((4-phenyl-5-oxo-3-pyrazolin-2-yl)-carbOnylamino)- Alpha -(1,4-cyclohexadien-1-yl)-methylpenicillin or the sodium salt thereof.
 47. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-benzyl-penicillin or the sodium salt thereof.
 48. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-benzylpenicillin or the sodium salt thereof.
 49. The compound according to claim 1 which is D(-)- Alpha -((4-phenyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-benzylpenicillin or the sodium salt thereof.
 50. The compound according to claim 1 which is D(-)- Alpha -((3-phenyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-benzylpenicillin or the sodium salt thereof.
 51. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-p-hydroxy-benzylpenicillin or the sodium salt thereof.
 52. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)- Alpha -(1,4-cyclohexadien-1-yl)-methylpenicillin or the sodium salt thereof.
 53. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-p-chloro-benzylpenicillin or the sodium salt thereof.
 54. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-p-nitro-benzylpenicillin or the sodium salt thereof.
 55. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-p-hydroxy -benzylpenicillin or the sodium salt thereof.
 56. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)- Alpha -(1,4-cyclohexadien-1-yl)-methylpenicillin or the sodium salt thereof.
 57. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-p-chloro -benzylpenicillin or the sodium salt thereof.
 58. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-p-nitro -benzylpenicillin or the sodium salt thereof.
 59. The compound according to claim 1 which is D(-)- Alpha -((3-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-benzylpenicillin or the sodium salt thereof.
 60. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-pyrazole-3-in-2-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 61. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-pyrazole-3-in-2-yl)-carbonylamino)-benzylpenicillin or the sodium salt thereof.
 62. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-carbonylamino)-benzyl-penicillin or the sodium salt thereof.
 63. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-carbonylamino)-p-hydroxy-benzylpenicillin or the sodium salt thereof.
 64. The compound according to claim 1 which is D(-)- Alpha -((5-oxo-3-pyrazolin-2-yl)-carbonylamino)- Alpha -(cyclohexa-1,4-dien-1-yl)-methylpenicillin or the sodium salt thereof.
 65. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-benzylpenicillin or the sodium salt thereof.
 66. The compound according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)-p-hydroxy -benzylpenicillin or the sodium salt thereof.
 67. The compOund according to claim 1 which is D(-)- Alpha -((4-methyl-5-oxo-3-pyrazolin-2-yl)-thiocarbonylamino)- Alpha -(cyclohexa-1,4-dien-1-yl)-methylpenicillin or the sodium salt thereof. 